Mechanical and electrical coupling of cardiac myocytes are essential properties which allow for the myocardium to function as a syncytium. Recent studies in man and animal models have shown that defects in proteins which orchestrate these properties can lead to cardiomyopathies or be the origin of arrhythmias. The intercalated disc located at the blunted, bipolar ends of the myocytes provide for both structural and electrical integrity of cardiac muscle. Within the disc are found three unique types ofjunctions: desmosomes, gap junctions and adherens junctions. Adherens junctions in the intercalated disk serve to strengthen the linkage of the contractile cells, bridging the contractile apparatus and actin-based cytoskeleton of adjacent cells. Gap junctions allow for rapid conductance of action potentials between myocytes. Stability of the myocyte is also maintained by cell-matrix interactions in costameres at the lateral surface of the cells. The focus of the current proposal is to define the functional role of two actin-linking proteins, vinculin and talin, which bind to each other, bridge the sarcomere to the cytoskeleton, function in cell-cell junctions and also in cell-extracellular matrix adhesion. These proteins each have variant forms that are highly expressed in heart, namely metavinculin and talin-2, respectively. Our global hypothesis is that vinculin, talin and their respective variant forms have unique role in the heart. To evaluate this hypothesis, three aims are proposed which make extensive use of unique mouse models. Theyare: 1) Assess how cardiac myocyte specific reduction of vinculin expression leads to abnormal cardiac function, predisposes to arrhythmias and functions in destabilization of the intercalated disk and cell-matrix adhesions, 2) Study the function of the muscle-specific splice-variant metavinculin as distinct from vinculin, and 3) Evaluate the role of talin-1 and talin-2 in cardiac myocytes. Metavinculin has been linked to cardiomyopathy in man. A better understanding of this group of related proteins will advance our understanding about the molecular basis of normal and abnormal cardiac function. It will also give insight to allow future development of directed heart failure therapies.